Antifungal resistance and stewardship: a knowledge, attitudes and practices survey among pharmacy students at the University of Zambia; findings and implications

Abstract Introduction Antifungal resistance (AFR) is a growing global public health concern. Little is currently known about knowledge, attitudes and practices regarding AFR and antifungal stewardship (AFS) in Zambia, and across the globe. To address this evidence gap, we conducted a study through a questionnaire design starting with pharmacy students as they include the next generation of healthcare professionals. Methods A cross-sectional study among 412 pharmacy students from June 2023 to July 2023 using a structured questionnaire. Multivariable analysis was used to determine key factors of influence. Results Of the 412 participants, 55.8% were female, with 81.6% aged between 18 and 25 years. Most students had good knowledge (85.9%) and positive attitudes (86.7%) but sub-optimal practices (65.8%) towards AFR and AFS. Overall, 30.2% of students accessed antifungals without a prescription. Male students were less likely to report a good knowledge of AFR (adjusted OR, AOR = 0.55, 95% CI: 0.31–0.98). Similarly, students residing in urban areas were less likely to report a positive attitude (AOR = 0.35, 95% CI: 0.13–0.91). Fourth-year students were also less likely to report good practices compared with second-year students (AOR = 0.48, 95% CI: 0.27–0.85). Conclusions Good knowledge and positive attitudes must translate into good practices toward AFR and AFS going forward. Consequently, there is a need to provide educational interventions where students have low scores regarding AFR and AFS. In addition, there is a need to implement strategies to reduce inappropriate dispensing of antifungals, especially without a prescription, to reduce AFR in Zambia.


Introduction
Antimicrobial resistance (AMR) is a term used to describe the ability of bacteria, fungi, parasites and viruses to overcome the lethal effects of antimicrobial agents. 1,24][5][6][7] Within AMR, antifungal resistance (AFR) is seen as an increasing problem; [8][9][10][11][12] however, the prevalence of AFR has been underestimated in the past. 13,14This misconception needs to be urgently addressed with a rise in fungal infections globally, particularly drug-resistant ones, further increasing morbidity and mortality rates from AMR. 9,[14][15][16][17] Currently, it is estimated that over 1.5 to 2 million people globally die each year from fungal infections, similar to the number of people dying each year from antibacterial resistance, with over a billion people currently affected by fungal diseases, which includes over 150 million people with severe fungal infections. 10,11,18,19The costs of treating patients with fungal diseases are also substantial, estimated at $6.7 billion-$7.2 billion annually in the USA alone in 2017 and 2018, 6,20 with these costs expected to rise with increasing AFR.
Despite rising mortality and costs due to AFR, most emphasis, research and public health policies have primarily been focused on resistance to antibacterials and antivirals as opposed to antifungals. 11,21This skew has had unintended consequences of leaving AFR relatively neglected compared with antibiotic resistance (ABR), which is despite increasing concerns with AFR. 9,13,22his oversight has serious implications for the overall management of fungal infections, although this is starting to change with, for instance, the call for more research on AFR and the introduction of stewardship programmes to improve the utilization of antifungals. 23For instance, in Zambia, Nowbuth et al., 24 in their recent systematic review on published studies regarding the prevalence of AMR in Zambia, did not find any studies on AFR meeting their inclusion criteria.However, published studies exist on other resistant pathogens. 244][35] However, achieving their optimal use remains a challenge. 36The use of antifungal medicines has increased in recent years due to the increased burden of fungal infections, especially among immunocompromised individuals. 21,35,373][44] Alongside this, an appreciable number of patients using antifungal treatments do so improperly, often failing to complete the full course, leading to AFR. 45,46 Furthermore, AFR fungi are typically resilient and transmissible human pathogens and thus potentiate the problem of AMR. 10,21,471][52][53][54][55][56][57] This situation is likely to worsen unless proactively addressed. 9he ever-growing problem of AFR requires development and successful implementation of multiple strategies within countries, especially among LMICs. 5,60,61The first step in this process is to assess current awareness, knowledge and attitudes towards antifungals and AFR among key stakeholder groups in order to develop pertinent interventions to reduce identified problems.Secondly, to develop and implement pertinent strategies, which could include educational strategies as well as targeted antimicrobial stewardship programmes (ASPs). 60,62,637][78] Consequently, we sought to address this evidence gap by initially assessing the knowledge, attitudes and practices (KAP) of student pharmacists at the University of Zambia regarding AFR and AFS.0][81] The findings can subsequently be used to refine educational programmes in universities to help improve antifungal utilization in the future.
3][84] In view of this, it is important that community pharmacists are fully conversant with key aspects of antifungals and AFR.We are aware in Zambia that up to 100% of pharmacies dispense antibiotics without a prescription. 857][88] In view of this, we believe the future pharmacists in Zambia should be able to provide appropriate advice to patients without unnecessarily exposing them to antifungals and AFR, especially those patients without medical prescriptions.

Study design, population and site
A cross-sectional study was conducted among undergraduate pharmacy students at the University of Zambia between June 2023 and July 2023, according to the STROBE guidelines.To be eligible, participants had to be enrolled and registered as undergraduate pharmacy students at the University of Zambia, with active participation after obtaining informed and written consent.
The sample size was estimated using Taro Yamane's formula, 89 by employing a finite population of 601 undergraduate pharmacy students stratified as 196 second-year students, 158 third-year students, 133 fourth-year students and 92 fifth-year students.After adjusting for a 10% non-response, our final minimum required sample size was 265 students.The study population was classified into strata based on the year of study.All participants were identified using class registers and were randomly sampled using computer-generated random numbers.

Data collection
Data were collected using an adapted questionnaire from two recent studies. 90,91Public health experts from the University of Zambia and the Copperbelt University subsequently reviewed the data collection tool for face and content validity.Hence, the questionnaire was prevalidated for simplicity, clarity, understandability, relevance and accuracy.The authors chose to adapt the data collection tools on AMR and AMS because there were no KAP studies that were done on AFR and AFS prior to the study.The questionnaire had four sections, namely: Section A: Sociodemographic characteristics of participants assessed using five questions; Section B: 10 questions on knowledge of AFR and AFS; Section C: 10 questions on attitude towards AFR and AFS; and Section D: 10 questions on practices regarding AFR and AFS.A pilot study was subsequently undertaken with 20 pharmacy students to improve the robustness of the questionnaire.Students who participated in the pilot study were excluded from the main study.The reliability of the questionnaire was determined using a Cronbach's α value.Hence, with a Cronbach's α value of 0.827 demonstrating an acceptable internal consistency, the final questionnaire was seen as reliable.The participants were recruited and provided with a self-administered questionnaire, which was submitted to the data collectors on completion.Data collection was undertaken by three data collectors (S.M., P.C. and W.M.) and lasted for 20 to 30 min per participant.A total of 420 questionnaires were administered to the identified participants.

Study measures
The main outcomes of this study were knowledge, attitudes and practices towards AFR and AFS (coded as good = 1, poor = 0).The KAP questions had three options (yes, no or neutral).Item scores were summed to obtain a composite score for each of the three options (Table S1, available as Supplementary data at JAC-AMR Online).The continuous scores were categorized to obtain binary variables for good knowledge, positive attitude and good practice using a cut-off value of 80%.We hypothesized that students with good knowledge and attitudes would have good practices towards AFR and AFS.In addition, the effect of knowledge on practice towards AFR and AFS will be mediated by students' attitudes (Figure 1).

Statistical analysis
We reported frequencies and percentages for categorical variables.The Pearson chi-squared test was used to compare scores of KAP among the students.KAP scores were calculated by adding correct responses to obtain a composite score.The scores were categorized into a binary variable using a cut-off value of 80% coded as ≥80% = 1 ('good knowledge, attitude and practice') and <80% = 0 ('poor knowledge, attitude and practice').Separate logistic regression models were used to calculate crude and adjusted ORs (AORs) with respective 95% CIs.All three multivariable models used significant variables at 20% from the univariable analysis.An investigator-led stepwise regression technique was used to drop off variables with high P values sequentially until a parsimonious model was built.Interactions were assessed between the final model's significant variables, and none reached any statistical significance.
We further conducted generalized structural equation modelling to assess the interrelationships between variables and their mechanisms of association.We calculated direct, indirect and total effects to examine how knowledge affected practice towards AFR and AFS, part of which could occur through attitude.The effect of knowledge on practice towards AFR and AFS while controlling for attitude is called the direct effect.On the other hand, the indirect effect occurs because knowledge affects the attitude, which in turn affects the practice towards antifungal resistance.Ultimately, the direct and indirect effects form the total effects on the outcome (practice towards AFR and AFS).All models were independently adjusted for year of study.Bootstraps (50 replications) were used to compute standard errors for effects estimates.All statistical analyses were performed in STATA (version 17; StataCorp LP), and the significance level was set at α less than 5%.

Ethics
This study was approved by the University of Zambia Health Sciences Research Ethics Committee (UNZAHSREC), approval number 2022112301176.Participants provided written informed consent after being informed of the purpose of this study.Participation in this study was voluntary and strictly for those who provided consent.

Characteristics of study participants
Of the 420 questionnaires distributed, 412 were completed and returned, resulting in a response rate of 98%.The majority of the participants were female (55.8%), aged between 18 and 25 years (81.6%),unmarried (91.8%) and resided in urban areas (80.6%) (Table 1).

KAP towards antifungals and AFR
Most students had good knowledge (85.9%), attitudes (86.7%) and practice (65.8%) towards AFR and AFS (Table 2).The highest proportion of participants who had good practice was among the third-year students (71.7%).There was no evidence though of an association between the year of study and scores for knowledge and attitudes.
This study found that 97.3% of the participants knew the definition of AFR, 93.7% could give examples of antifungals, 93.9% knew that misuse of antifungals contributes to AFR, and 89.3% knew that AFR can lead to prolonged illnesses and higher mortality.The lowest score among students concerned over-the-counter antifungal medicines not leading to AFR (Table 3).
Most of the participating pharmacy students (90.1%) knew that AFR is a significant public health concern; however, the majority (51.2%) felt that the current training on antifungals and AFR in the university was not sufficient.Most students (89.8%) were also aware that the misuse and overuse of antifungals contributed to AFR, and 90.5% believed that infection prevention and control measures could help address AFR (Table 3).
This study also found that the prevalence of accessing antifungal medicines without a prescription was 30.2%.Additionally, 73.5% of participants did not recommend antifungals to their families or friends, did not use antifungals for UTIs, did not use antifungals when they had a cold, and did not participate in Antifungal resistance and stewardship any AFSPs.Finally, 81.1% reported that they sought additional education or training on antifungals and AFR (Table 3).

Factors associated with KAP towards AFR and AFS
Table 4 shows the results from the multivariable analysis.Male participants were less likely to report good knowledge of AFR and AFS than female participants (AOR = 0.55, 95% CI: 0.31-0.98).Similarly, fourth-year students versus second-year students (AOR = 0.44, 95% CI: 0.20-0.98)and students residing in urban areas versus rural/peri-urban (AOR = 0.35, 95% CI: 0.13-0.91)were less likely to report a positive attitude.

Mediation analysis: effect of knowledge on the practice towards AFR and AFS
Mediation analysis was performed to examine if attitude is a mechanism through which knowledge could affect the practice towards AFR and AFS (Table 5).Good knowledge was significantly associated with good practice, both directly and indirectly, through attitude.The total effect of good knowledge and attitude on good practices was 1.47-fold.

Discussion
To the best of our knowledge, this is the first study to assess the KAP of undergraduate pharmacy students regarding AFR and AFS in Zambia.Approximately 86% of participating students reported good knowledge and attitude towards AFR and AFS, with approximately 66% reporting good practice.Male students were less likely to report good knowledge of AFR and AFS than female students.Similarly, fourth-year students versus second years, and students residing in urban areas, were less likely to report positive attitudes.Furthermore, fourth-year students compared with second-year students were less likely to report good practices.In mediation analysis, good knowledge was significantly associated with good practice, both directly and indirectly, through attitude.
2][93][94] However, our findings were better than those seen in other studies involving students. 95,96The good knowledge reported in our study may be because pharmacy students in Zambia are exposed to information about antifungals, antibiotics, antivirals and antiprotozoal drugs during training.Reassuringly as well, most pharmacy students knew the term AFR, examples of antifungals, factors that promote AFR, and AFS as a strategy for combating this public health issue.These findings corroborate similar studies where students knew the definition of AMR and predisposing factors as well as AMS/ASPs as ways forward to combat this public health problem. 97,98nterestingly, fourth-year students in our study were less likely to report good practices than second-year students, which contrasts with a study in Ghana that found that the level of AMR and AMS knowledge correlated with the year of study. 91dditionally, female students were more likely to have good knowledge of AFR and AFS than male students.This could be because female individuals tend to seek medical help and visit healthcare facilities where they are likely to receive information about antifungal medicines.Mudenda et al.
The present study found that most students had positive attitudes towards AFR and AFS, similar to previous studies on AMR in Zambia. 79,80However, our study found positive attitudes compared with the negative attitudes towards AMR and ABR among students in China. 32Despite most students having positive attitudes towards AFR and AFS in our study, 51.2% felt that the training they received on antifungals, AFR and AFS was insufficient.However, this is similar to a study in Colombia where most students felt the information they received on AMR and AMS during training was insufficient. 99Consequently, this calls for improved AMR and AMS information in undergraduate curricula in Zambia and beyond as well as integrating AFR into the curricula.We will continue to monitor this in the future.
The present study found slightly lower scores in practices of students regarding AFR and AFS compared with the scores in knowledge and attitudes, which also needs addressing when updating the curricula.Intriguingly, we found that 30.2% of the students had purchased antifungals without a prescription.This is Antifungal resistance and stewardship only important if antifungals were inappropriate for the infection, with countries typically making antifungals available over the counter.We are aware of the appreciable misuse and overuse of antifungals, which needs to be avoided to reduce AFR.Our findings also revealed that very few students participated in AFS and awareness programmes.Additionally, very few students updated themselves about the latest research and guidelines regarding antifungal medications and AMS.These behaviours contributed to the low scores in practice recorded among the study participants.Community pharmacists and their assistants can play a key role here.Consequently, it is important that student pharmacists participate in AFS and awareness programmes during their training, which was not the case in our study.In addition, students pharmacists must take part in AFSPs to improve the future use of antifungals to reduce AFR.Alongside this, the students must update themselves on the latest research and guidelines to improve the care of patients, which is not happening currently.
One surprising finding of our study was that fourth-year students reported lower rates of good practices compared with their second-year counterparts.This is because fourth-year students, having had more exposure to clinical settings, may feel overconfident and more inclined to self-medicate, leading to poor practices for themselves and patients post-qualification.1][102][103] The observed variations suggest that educational strategies, and their impact on students' practices, can differ by region and institution; consequently, any updated educational input needs to be targeted to the specific student body in question.Future research should explore the underlying reasons for this discrepancy to inform the development of more effective educational programmes.
Additionally, organizations such as the Pharmaceutical Society of Zambia (PSZ) should introduce short courses and continuing professional development (CPD) programmes that focus on AFS and the role of AFS.The Ministry of Health and the Zambia National Public Health Institute (ZNPHI) should also champion the promotion of research and awareness campaigns on AFR and support AFSPs. 22e are aware that there are limitations in our study.Firstly, the study was only conducted at a single university in Zambia.This implies that the findings of our study may not be generalized to all the universities in Zambia.Secondly, we employed a quantitative, cross-sectional design, which may constrain the depth of information gathered.The approach we used in our study may affect the depth of findings as participants are not allowed to give their detailed opinion on a subject matter.Despite these limitations, since our study is the first to highlight students' KAP concerning AFR and AFSPs in Zambia, we believe the findings can serve as an impetus for researchers, health authorities and policymakers to integrate AFR into programmes to address AFR in Zambia and beyond.Further, we recommend multicentre studies on AFR and AFS among students in all universities in Zambia.Further, future studies should be conducted to explore the KAP of healthcare professionals on AFR and AFS.The model was adjusted for year of study.

Table 2 .
Students' KAP according to the year of study

Table 3 .
Students' responses to the KAP statements

Table 5 .
Mediation analysis of the influence of knowledge on the practice towards AFR and AFS

Table 4 .
Predictors of good KAP among Bachelor of Pharmacy students AOR, adjusted odds ratio; 95%CI, 95% confidence intervals.Boldface indicates statistical significance at 5%.Good knowledge, attitude and practice were scores of 80% or above.ConclusionsOverall, most students possessed good knowledge and attitudes towards AFR and AFS, which is encouraging since AFR and AFSPs are a poorly researched and under-researched field across Africa including Zambia.This underscores the need for targeted educational interventions in areas where students scored poorly such as insufficient training on AFR, not participating in AFS, not being up to date with information on AFR and AFS, and addressing access to antifungals without prescriptions.